Cigarette smoking has many adverse consequences. In addition to being one of the major preventable causes of death in the United States from lung cancer and coronary artery disease, smoking has been implicated in cancers of the larynx, pancreas, bladder, kidney, and cervix. Smoking during pregnancy has been shown to increase the incidences of still births, neonatal deaths, premature delivery, low birth weight, and fetal death. Smoking also has adverse impacts on breast feeding: it reduces milk production, decreases the milk's vitamin C content, and increases colicky pain and diarrhea in the breast-fed infant. Hospital admissions for bronchitis and pneumonia are twice as high for children whose parents smoke. These children also have increased risk of cancer later in life.
Despite the potential adverse health effects to the smoker and smoker's family, the vast majority of cigarette smokers are unable to cease smoking. The lack of smoking cessation success is attributed, in part, to nicotine addiction. One third to one half of occasional cigarette smokers graduate to maladaptive use and to physical dependence on nicotine. In fact, addiction to nicotine, as described in past U.S. Surgeon General's reports on smoking, is widespread, with over 50 million smokers in the United States alone. As a result of the effects of nicotine, most tobacco-dependent persons never achieve lasting abstinence, and half of all smokers die prematurely of tobacco-related disease.
Greater understanding of the adverse health effects of tobacco consumption has led to an increase in research on the nature of nicotine addiction and its treatment.
Nicotine is a water-soluble and lipid-soluble base. When delivered in alkaline cigar and pipe smoke, smokeless tobacco, and some European cigarettes, nicotine is readily absorbed across the mucosal membranes of the mouth and nose, which explains the rapid absorption associated with smokeless tobacco. Cigarette smoke is acidic and must be inhaled to be absorbed effectively in the pulmonary alveoli, where absorption is rapid. From the lung, nicotine is absorbed into alveolar capillary blood and carried to the heart and then to the brain and other organs.
All widely marketed cigarettes deliver sufficient nicotine to establish and sustain dependence readily. Cigarettes contain 6 to 11 mg of nicotine, of which the smoker typically absorbs 1 to 3 mg, irrespective of the nicotine-yield ratings provided by the tobacco company. The typical pack-per-day smoker absorbs 20 to 40 mg of nicotine each day, achieving plasma concentrations of 25 to 35 ng per milliliter by the afternoon. The plasma half-life of nicotine is approximately two hours.
The effects of nicotine that are associated with dependence include increased expression of brain nicotine receptors, changes in regional brain glucose metabolism, electroencephalograph changes, the release of catecholamines, tolerance, and physiologic dependence. These effects increase the compulsion to smoke by producing positive reinforcement (with the administration of nicotine) and withdrawal symptoms (with abstinence).
Withdrawal symptoms are intensified by abrupt abstinence from nicotine, beginning within a few hours, peaking within a few days, and typically lasting for four weeks, although there is considerable variability. Most people who quit smoking relapse within one week, when withdrawal symptoms are at or near their peak. Thereafter, the correlation between withdrawal symptoms and relapse is weak.
Although a variety of approaches have been used to treat nicotine dependency, none have proven widely successful. They include stopping "cold turkey", hypnosis, electroshock, acupuncture, behavioral counseling, as well as various forms of therapeutic support. Nicotine replacement therapies, such as via transdermal patches or nicotine gum, in conjunction with behavioral counseling are now commonly used to treat nicotine withdrawal and to aid smoking cessation.
Nicotine gum and transdermal nicotine delivery systems decrease abstinence discomfort, especially anxiety, decreased memory, and irritability. However, they do not reliably decrease weight gain or craving, and they are unable to mimic the high plasma concentrations of nicotine which is experienced when nicotine is delivered by smoking. Moreover, discontinuing the use of nicotine gum can lead to the same withdrawal symptoms as those experienced after cigarette withdrawal. In addition, since nicotine is toxic, the availability of nicotine gum or patches poses a risk of poisoning to children and pets.
Another method for treating nicotine addiction involves the administration of lobeline, an alkaloid obtained from the dried leaves and tops of the Indian tobacco herb, Lobelia inflata. Lobeline is a substituted piperidine compound that produces several physiological affects, some of which are similar to those produced by nicotine. Because of lobeline's pharmacological similarities with nicotine, it has been considered as a substitute for nicotine which assists individuals in lessening addiction to nicotine and in ceasing to smoke cigarettes. However, lobeline's potency in causing these physiological effects is significantly less than that of nicotine. Furthermore, although use of lobeline as a smoking cessation aid has been studied since at least the 1930's, its efficacy has been a matter of dispute. Moreover, severe, undesirable side-effects have been reported.
Although nicotine withdrawal symptoms are, in many respects, similar to those experienced during withdrawal from other addictive substances, including decreased heart rate, anxiety, tension, difficulty concentrating, impatience, depression, increased appetite with accompanied weight gain, irritability, and restlessness, treatment modalities used for other addictions (e.g., cocaine, amphetamine, or opiate addiction) have not found application in the treatment of nicotine addiction.
Studies designed to elucidate the mechanism of nicotine's addictive powers and to correlate this mechanism with those of other addictive substances (e.g., cocaine, amphetamines, or opiates) have been inconclusive. For example, several studies have suggested that nicotine dependence, like cocaine dependence, may be attributed to a reinforcing effect mediated by an increase in dopamine in the brain. Other studies (e.g., Corrigall et al., "Selective Dopamine Antagonists Reduce Nicotine Self-Administration," Psychopharmacology, 104:171-174 (1991)), however, have shown that the effects of dopamine antagonists on nicotine self-administration are different from the effects of these antagonists on cocaine self-administration. For instance, in self-administration studies with cocaine, treatment with dopamine antagonists usually leads to compensatory increases in the amount of cocaine administered. Similarly, animals appear to adjust their cocaine self-administrating response fairly precisely when the dose is changed. However, no such degree of regulation in nicotine self-administration was observed. In fact, the same doses of dopamine antagonists which produce compensatory increases in cocaine self-administration actually produce decreases in nicotine self-administration. Consequently, it appears that the dopamergic responses to nicotine and cocaine are different.
In view of the serious health effects of nicotine dependency and the limitations of presently-available methods for treating this addiction, a need remains for effective methods of reducing nicotine addiction. The present invention is directed to meeting this need.